Despite steady progress over the past 15 years on the symptomatic treatment of Alzheimer's disease (AD), there is currently no treatment that modifies the course of this disease. Because of the key role of the amyloid-beta (A?) peptide in the pathophysiology of AD, A? synthesis, deposition and clearance have become important targets for the development of new therapies. This application proposes to optimize the in vivo anti-amyloid properties of several lead small molecule A?-binding agents (SMApBAs) in the PSAPP transgenic mouse model of amyloid deposition. These agents are third and fourth generation Congo red derivatives that structurally resemble the natural product, curcumin. As part of a program to develop in vivo amyloid imaging agents, these compounds were designed to have high affinity for A?, good brain entry, and specifically label A? deposits m vivo. In vitro studies have shown that this class of compounds possesses anti-aggregation and anti-oxidant effects and protects cells from toxic actions of A?. In preliminary studies with PSAPP mice, several SMA?BAs reduced soluble and insoluble A? levels by 50-75%. We hypothesis that the in vivo amyloid-clearing effect of these SMA?BAs will be cooperative with amyloid clearance by immunotherapy because the SMA?BAs may increase the proportion of total A? that resides in the soluble pool, thus making more A? available for enhanced peripheral clearance by vascular antibodies. In this application, we propose to complete the development of the three currently most promising lead compounds (and two out of a group of 24 newly synthesized analogs of these three) to the point where one compound is ready for subsequent animal toxicology and phase I human studies. We propose to do this by: 1) extending our preliminary anti-amyloid studies in larger numbers of PSAPP mice, treated at older ages, for longer periods of time and with newly developed SMA?BAs; 2) performing dose-response and oral efficacy studies of the two most promising agents; 3) assessing the cooperativity of SMA?BA and passive immunization treatment; and 4) assessing the absorption, distribution, metabolism and elimination (ADME) and acute rotorod neurotoxicity of the two most effective lead SMA?BA's and optimizing the chemical synthesis of the best compound in preparation for GMP production. Building on the drug development expertise that produced the human amyloid imaging PET tracer Pittsburgh Compound-B (PIB), we have assembled a team with the additional expertise required for this project and have already initiated studies of the type proposed in this application. This team combines expertise in medicinal and radiochemistry, neuropharmacology, pharmacokinetics and drug metabolism, histopathology, molecular [unreadable] biology of amyloid, clinical trial design and clinical neurology and psychiatry. [unreadable] [unreadable] [unreadable]